The background description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the present disclosure.
The normal function and structure of microvessels are crucial to the survival of tissue cell due to essential nutrients passing through their walls. Structural and functional cerebromicrovascular abnormalities are implicated in the pathogenesis of brain diseases. See, for example, Perlmutter, L. S. and Chui, H. C., 1990, Microangiopathy, the vascular basement membrane and Alzheimer's disease: a review, Brain Res Bull. 24, 677-686; Buee, L., H of, P. R. and Delacourte, A., 1997, Brain microvascular changes in Alzheimer's disease and other dementias, Ann N Y Acad Sci. 826, 7-24; and Serne, E. H., de Jongh, R. T., Eringa, E. C., R G, I. J. and Stehouwer, C. D., 2007, Microvascular dysfunction: a potential pathophysiological role in the metabolic syndrome, Hypertension. 50, 204-211, the disclosures of which are incorporated herein by reference in their entirety.
Imaging methods for assessing the cerebromicrovasculature is therefore important in a wide range of clinical and neuroscience-research fields. The most commonly used magnetic resonance angiography (MRA) techniques to visualize the vasculature are time-of-flight MRA (TOF-MRA) and contrast-enhanced MRA (CE-MRA). TOF-MRA depends on the motion of water protons in inflowing blood, which is sensitive to rapidly inflowing spins (i.e., in arteries), whereas CE-MRA employs contrast agents to detect low flow rates in veins. See, for example, Reese, T., Bochelen, D., Sauter, A., Beckmann, N. and Rudin, M., 1999, Magnetic resonance angiography of the rat cerebrovascular system without the use of contrast agents, NMR Biomed. 12, 189-196; and Miraux, S., Serres, S., Thiaudiere, E., Canioni, P., Merle, M. and Franconi, J. M., 2004, Gadolinium-enhanced small-animal TOF magnetic resonance angiography, Magma. 17, 348-352, the disclosures of which are incorporated herein by reference in their entirety.
The abilities of these methods to view larger arteries or veins have been demonstrated, and have been used to study tumor-related vasculature, transient focal ischemia, and genetic variations of the vascular structure. See, for example, van Vliet, M., van Dijke, C. F., Wielopolski, P. A., ten Hagen, T. L., Veenland, J. F., Preda, A., Loeve, A. J., Eggermont, A. M. and Krestin, G. P., 2005, MR angiography of tumor-related vasculature: from the clinic to the micro-environment, Radiographics, 25 Suppl. 1, S85-97, discussion S97-88; Beckmann, N., 2000, High resolution magnetic resonance angiography non-invasively reveals mouse strain differences in the cerebrovascular anatomy in vivo, Magn Reson Med. 44, 252-258; Besselmann, M., Liu, M., Diedenhofen, M., Franke, C. and Hoehn, M., 2001. MR angiographic investigation of transient focal cerebral ischemia in rat, NMR Biomed. 14, 289-296; and Brubaker, L. M., Bullitt, E., Yin, C., Van Dyke, T. and Lin, W., 2005, Magnetic resonance angiography visualization of abnormal tumor vasculature in genetically engineered mice, Cancer Res. 65, 8218-8223, the disclosures of which are incorporated herein by reference in their entirety.
However, since TOF-MRA signals are naturally related to high-flow-rate vessels, they have limitations in visualizing small vessels even at high resolution, and suffer from flow-related artifacts including signal loss in areas with turbulent flow and motion artifacts from pulsatile flow. For example, see Pipe, J. G., 2001, Limits of time-of-flight magnetic resonance angiography, Top Magn Reson Imaging 12, 163-174, the disclosure of which is incorporated herein by reference in its entirety. CE-MRA with the injection of Gd-DTPA, which has a short intravascular (IV) half-life and rapidly redistributes into the extracellular space, may not satisfy the long acquisition time required for high-resolution MRA applications.